Pharmacology · Antipsychotic Drugs

First-Generation Antipsychotics

Potency classification, key agents, extrapyramidal syndromes, and serious adverse effects

Potency in this class has a precise meaning that differs from common usage. It refers exclusively to the milligram dose required to reach therapeutic D2 receptor occupancy — not to how well an agent works. Haloperidol at 5 mg and chlorpromazine at 500 mg are equally effective antipsychotics; what differs is the receptor affinity and consequently the whole adverse effect profile that comes with each.
The potency table is color-coded to show that high-potency and low-potency agents trade one adverse effect burden for another. High-potency agents carry high extrapyramidal risk but low sedation, anticholinergic, and orthostatic burden. Low-potency agents reverse this: lower motor risk, but the sedation and autonomic effects that follow from broad receptor coverage.
The three extrapyramidal syndrome cards are ordered by time of onset because the temporal sequence is the key to distinguishing them clinically and choosing a response. Dystonia within hours, akathisia within days to weeks, drug-induced parkinsonism within weeks — each has a different treatment and a different misidentification risk.
Akathisia deserves the emphasis it gets in its card. It is the most common reason patients stop taking antipsychotics, and its inner restlessness is frequently mistaken for worsening psychosis — leading to dose increases that make it worse rather than better.
The two serious adverse effect cards are a deliberate contrast pair. Neuroleptic malignant syndrome is acute and life-threatening, characterized by rigidity distinguishing it from serotonin syndrome. Tardive dyskinesia is the opposite: slow onset, potentially irreversible, and driven by D2 receptor supersensitivity from the same chronic blockade that treats the disease.

Potency Classification and Adverse Effect Profile

Agent	Dose Range	Extrapyramidal Symptom Risk	Sedation	Anticholinergic	Orthostatic Hypotension
High-Potency Agents — selective D2 blockade
Haloperidol	2–20 mg/day	High	Low	Low	Low
Fluphenazine	2–20 mg/day	High	Low	Low	Low
Perphenazine	8–64 mg/day	Moderate	Moderate	Low	Moderate
Low-Potency Agents — broad receptor blockade (D2 + H1 + M1 + alpha-1)
Chlorpromazine	200–1000 mg/day	Low–Moderate	High	High	High
Thioridazine	200–800 mg/day	Low	High	Highest	High

Extrapyramidal Syndromes — Time Course and Management

Onset: Hours to Days

Acute Dystonia

Sustained muscle contractions, abnormal postures
Oculogyric crisis, torticollis, opisthotonus
Laryngeal dystonia — airway emergency
Risk: young males, antipsychotic-naive patients
Treat: Benztropine or diphenhydramine intramuscularly or intravenously — rapid effect
Mechanism: Relative cholinergic excess from acute D2 blockade

Onset: Days to Weeks

Akathisia

Subjective inner restlessness, urge to move
Pacing, inability to sit still
Leading cause of non-adherence
Danger: mistaken for worsening psychosis → dose escalation worsens it
Treat: Propranolol first-line; dose reduction; short-term benzodiazepines
Note: Anticholinergics not first-line for akathisia

Onset: Weeks

Drug-Induced Parkinsonism

Bradykinesia, rigidity, resting tremor
Indistinguishable from Parkinson disease at examination
Higher risk in elderly patients
Dose-dependent; reversible with dose reduction
Treat: Dose reduction preferred; benztropine or amantadine if needed
Caution: Anticholinergics worsen cognition in elderly patients

Serious Adverse Effects — Neuroleptic Malignant Syndrome and Tardive Dyskinesia

Neuroleptic Malignant Syndrome

Timing: Acute — days to weeks from initiation
Tetrad: Hyperthermia + Lead-pipe rigidity + Autonomic instability + Altered consciousness
Lab: Markedly elevated creatine kinase (rhabdomyolysis)
vs. Serotonin syndrome: Rigidity + bradyreflexia (not hyperreflexia/clonus)
Treatment: Stop antipsychotic immediately; dantrolene; bromocriptine; intensive care unit support
Incidence: 0.01–0.02% — rare but life-threatening

Tardive Dyskinesia

Timing: Late — months to years of exposure
Movements: Repetitive, involuntary orofacial movements (lip smacking, tongue protrusion); choreiform limb movements
Mechanism: D2 receptor upregulation (supersensitivity) from chronic blockade
Risk factors: Older age, female sex, high-potency agents, longer duration
Treatment: Minimize dose or switch; vesicular monoamine transporter 2 inhibitors (valbenazine, deutetrabenazine) for established cases
May be irreversible — prevention is the goal

Potency Rule: High-potency agents (haloperidol, fluphenazine) = high extrapyramidal symptom risk, low sedation/anticholinergic burden. Low-potency agents (chlorpromazine, thioridazine) = lower extrapyramidal symptom risk, high sedation/anticholinergic/orthostatic burden. Potency predicts adverse effect profile, not antipsychotic efficacy.

Unique to thioridazine: QTc prolongation / torsades de pointes (hERG blockade) + pigmentary retinopathy at high doses. Last-resort agent requiring baseline electrocardiogram.

Suggested References

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